PIK3CA

PIK3CA is a gene that gives your cells instructions for how to make a protein called p110 alpha. This protein is part of an enzyme called PI3K. PI3K helps control how your cells grow, divide and survive.

Sometimes, changes (variants) in the PIK3CA gene can make the PI3K enzyme too active. When this happens, cells may grow or divide too much. This can lead to certain cancers and overgrowth conditions.

What does PIK3CA stand for?

PIK3CA stands for phosphatidylinositol 3-kinase catalytic subunit alpha:

• P = Phosphatidyl
• I = Inositol
• K = Kinase
• 3 = Refers to the 3-position on the inositol ring (where the enzyme adds a phosphate group)
• C = Catalytic
• A = Alpha

That’s a long name, but it basically describes what the gene does. It helps make the alpha part of an enzyme called phosphatidylinositol 3-kinase (PI3K).

What is PIK3CA-related overgrowth spectrum?

PIK3CA-related overgrowth spectrum (PROS) is a group of rare genetic conditions. They occur when changes are made to the PIK3CA gene. These changes make parts of your body grow too much. This can affect your muscles, bones, fat, nerves, brain, blood or lymph vessels.

The changes only happen in some cells. So, overgrowth often appears on one side of your body. Or the changes can affect specific areas, like your arm or a part of your face. Not all of these changes are always visible when you look at someone.

There are many types of PROS, based on the areas of your body and tissues affected. Many healthcare providers are moving away from using specific syndrome names. Instead, they’re referring to symptoms as being related to PROS, in general. But you may also hear or read about:

• CLAPO syndrome: CLAPO causes port wine stains in your lower lip and malformations in your face and neck. Your face, arms and legs may not be even.
• CLOVES syndrome: CLOVES causes swelling in your trunk and/or overgrowth of your arms or legs. You may also have blood vessel (vascular) malformations and bumpy, brown or gray birthmarks.
• Klippel-Trenaunay syndrome (KTS): KTS causes port wine stains and other blood vessel issues. You may also have bone and soft tissue overgrowth.
• Diffuse capillary malformation with overgrowth (DCMO): DCMO causes port wine stains and overgrowth over a large area of your body.
• Fibro-adipose vascular anomaly (FAVA): FAVA leads to masses of fatty tissue and blood vessels within your muscles. This can cause pain and affect your ability to move.
• Fibroadipose hyperplasia (FAH): FAH causes patches of overgrowth in your arm, leg or another body part. It happens due to the overgrowth of fatty connective tissue.
• Hemihyperplasia multiple lipomatosis syndrome (HHML): HHML causes multiple fatty growths. It leads to the enlargement of your arm, leg or another body part.
• Macrodactyly: Macrodactyly causes one or more fingers or toes to enlarge. This can lead to pain and reduced mobility. It happens due to the overgrowth of bone and soft tissue.
• Muscular hemihyperplasia (HH): HH causes the muscles on one side of your body to overgrow. It often overlaps with FAH, HHML and/or macrodactyly.
• Facial infiltrating lipomatosis (FIL): FIL causes your face to be uneven. Your face, tongue and teeth also enlarge. It happens due to the overgrowth of bone and fatty tissue in your face.
• Lipomatosis of nerve (LON): LON causes pain and numbness around your nerve bundles. This is due to the overgrowth of fatty tissue. It most commonly affects your median nerve.

There are also several overgrowth conditions that affect your brain. These can cause seizures and intellectual disabilities due to brain enlargement.

Symptoms of PROS

The signs and symptoms of PROS can vary widely. It depends on the specific PIK3CA disease-causing variant and the body parts it affects. Some common symptoms include:

• Overgrowth of your face, arms, legs or other body parts
• Enlarged brain, heart, liver or other organs
• Bone malformations, like scoliosis
• Blood vessel abnormalities, like birthmarks or enlarged blood vessels that may not work properly
• Blood clots
• Seizures
• Intellectual disabilities

What causes PIK3CA-related overgrowth spectrum?

A change (variation) in the PIK3CA gene causes PROS. These changes are called somatic mutations. That means you don’t get them from your biological parents. Instead, these changes occur sometime during in utero development.

The changes cause the PI3K enzyme to become too active. When that happens, the enzyme sends strong “grow and divide” signals to cells even when it shouldn’t.

Along with PROS, a PIK3CA gene mutation can also be found in certain cancers. This doesn’t mean that someone with a PIK3CA variant related to PROS has cancer or is at an increased risk of getting cancer.

How is PIK3CA-related overgrowth spectrum diagnosed?

Your healthcare provider will perform a biopsy of the affected tissue to look for a change in the PIK3CA gene. You may also have imaging tests to look for bone overgrowth or other malformations.

In some cases, your provider may be able to diagnose the condition with prenatal ultrasound. This test can sometimes find growth abnormalities.

How is PIK3CA-related overgrowth spectrum treated?

Treatment depends on the type of PROS condition and your symptoms. Certain medicines can help slow down or even turn off the overactivity of the PI3K enzyme. For severe cases, providers use a PIK3CA inhibitor called alpelisib. The U.S. Food and Drug Administration (FDA) approved this medication for adults and children age 2 and up in 2022.

Other PROS treatment options include:

• Debulking surgery: To remove larger growths
• Laser ablation: To lighten the color of vascular malformations
• Epiphysiodesis: To treat bony overgrowth in your arm or leg
• Sclerotherapy: To treat malformations affecting your deep veins
• Embolization: To treat malformations affecting your deep arteries
• Shunt placement: To drain excess cerebrospinal fluid from your head
• Compression therapy: To wrap affected areas (like your arm or leg) to reduce pain and swelling
• Anticoagulation therapy: To take medication that reduces the risk of blood clots and, in turn, reduces pain

Your provider may also recommend physical, occupational or speech therapy.

What is the prognosis for PIK3CA-related overgrowth spectrum?

The outlook for PROS varies widely because it’s a spectrum of conditions. People with mild symptoms may have a typical life expectancy. People with more severe types of PROS conditions may experience long-term health complications that can affect their life expectancy. Factors that affect your outcome include:

• Type of PROS condition
• Tissues and organs affected
• Severity of your symptoms
• When you were diagnosed
• Whether you’ve developed complications